Imidazole-type antifungal compounds, as worldwide, leading antifungal agents, are those having an imidazole group in the chemical structure thereof. They have been believed to exhibit an antifungal activity mainly by damaging the cell membrane of fungi.
For those imidazole-type antifungal agents, there have been suggested as an active ingredient for OTC drugs clotrimazole, miconazole nitrate, econazole nitrate, bifonazole, oxiconazole nitrate, sulconazole nitrate, tioconazole and the like.
Clotrimazole has been applied as external preparations solely and is effective against Trichophyton and also Candida. If applied to the healthy skin, in vivo absorption of the agent can hardly be observed, while local side-effects such as irritating feeling, flare, anthema and the like in the skin are believed to be manifested as a direct irritating effect on the skin or allergic effect.
Bifonazole exhibits a similar action to that of clotrimazole and is effective for many human pathogenic fungi. It is said that this agent possesses a more excellent skin permeability in external use and a higher drug retention in the cutaneous tissues as compared with other imidazole-type antifungal agents. As is similarly seen with clotrimazole, local side-effects such as irritating feeling, flare, anthema and the like in the skin are manifested.
Miconazole nitrate and econazole nitrate exert an antifungal activity against Trichophyton, Candida, Aspergillus, Cryptococcus and others. When applied to the healthy skin, in vivo absorption of these agents can hardly be observed, while similar local side-effects to those of clotrimazole are observed and a very few systemic side-effects are observed, when applied externally in a conventional manner.
The term a quaternary ammonium salt as used herein refers to a cationic surfactant which is a quaternary ammonium salt. It may include benzethonium chloride, benzalkonium chloride, dequalinium chloride and the like. It has been supposed that the cation released from the quaternary ammonium salt might be adsorbed on the microbial surface and then carried into the cells to affect the cellular proteins, whereby an antifungal activity could be exerted.
Benzethonium chloride and benzalkonium chloride exert an antimicrobial activity against gram bacteria and fungi, while it is known that long term application of these agents to the skin brings about side-effects of hypersensitiveness such as chapped skin, flare, itching and others.
Dequalinium chloride has been reported to exert an antimicrobial activity against bacteria (especially, Staphylococcus aureus and hemolytic streptococci) and fungi. It has been dispensed mainly for buccal antifungal agents or antiodontalgic and antipyorrheal agents.
Although there has not yet been reported a medicament wherein an imidazole-type antifungal compound is blended or combined with a quaternary ammonium salt, U.K. Patent No. 2 208 598A discloses a combination of an imidazole-type antifungal compound with salicylic acid or benzoic acid.